The Bcl-2 gene family
The bcl-2 gene family encodes a divergent group of proteins that regulate programmed cell death (apoptosis).
One arm of this family (including mammalian Bcl-2) is required for cell survival; in contrast, two subgroups of the Bcl-2 family are both required for apoptotic cell death.
The role of Bcl-2 in apoptosis
Bcl-2 plays a pivotal role whitin the intrinsic pathway, which requires the release of mitochondrial proteins, such as Cytochrome c, working together with the other two cytosolic protein factors, Apaf-1 (apoptoic protease activating factor-1) and procaspase-9, to promote the assembly of a caspase-activating complex termed the apoptosome, which in return induces activation of caspase-9 and thereby initiates the apoptotic caspase cascade.
Interacting with Bax, Bcl-2 inhibits its pro-apoptotic activity, by inhibiting Bax-mediated cytochrome C release.
The role of Bax and Bak in tumourigenesis
Since over-expression of Bcl-2-like proteins promotes tumourigenesis, it is possible that pro-apoptotic Bcl-2 family like Bak and Bax members can function as tumour suppressors.
Experiments in some mouse models of cancer development have suggested that Bax can function as a tumour suppressor; loss of Bax was found to accelerate tumourigenesis in transgenic mice expressing a truncated version of the SV40 large T antigen that blocks Rb but not p53 activity.
This study demonstrated that:
- Loss of Bax reduces p53-induced apoptosis;
- Bax deficiency does not accelerate tumourigenesis on a p53−/− background.
Bcl-2 and GSH
It has been reported that over-expression of Bcl-2:
- leads to an increase in total cellular glutathione (GSH) levels;
- alters GSH compartmentalization (leading to a relocalization of GSH into the nucleus).
Recently, has been reported that Bcl-2 over-expression increases intracellular glutathione by inhibiting methionine
efflux (this hypothesis has been demonstrated in HeLa cell line
Moreover, exogenous GSH blocked apoptotic changes and caspase activity in isolated nuclei exposed to the pro-apoptotic protease granzyme B.
These findings indicate that one of the functions of Bcl-2 is to promote sequestration of GSH into the nucleus, thereby altering nuclear redox and blocking caspase activity as well as other nuclear alterations characteristic of apoptosis.
This mechanism could contribute to the suppression of apoptosis in cells with elevated Bcl-2 levels.
The role of the Bcl-2 protein family in cancer
Bcl-2 expression causes redistribution of glutathione to the nucleus.
Expression of Bcl-2 Increases Intracellular Glutathione by Inhibiting Methionine -Dependent GSH Efflux